Transport characteristics of 5-aminosalicylic acid into colonic epithelium: Involvement of sodium-coupled monocarboxylate transporter SMCT1-mediated transport system

5-Aminosalicylic acid (5-ASA) is conventionally used as a first line drug for inflammatory bowel disease (IBD). Because 5-ASA is well absorbed in the small intestine, very high dose of 5-ASA is required to deliver it to the large intestine which is a target site. Interestingly, 5-ASA is reported to be transported into the large intestine as well as the small intestine via unknown transport system. In a heterologous expression system using Xenopus oocytes, sodium-coupled monocarboxylate transporter 1 (SMCT1) has been reported to accept 5-ASA as a substrate. Although SMCT1 is found to be expressed in the large intestine, it is unknown whether SMCT1 is responsible for 5-ASA absorption from the large intestine or not. Here we determined the transport characteristics of 5-ASA in the isolated everted sac prepared from mouse large intestine. Na+-dependent uptake of [3H] nicotinate, a substrate for SMCT1, in mouse colon was competitively inhibited by 5-ASA with IC50 value of 2.8 mM. In addition to nicotinate, 5-ASA uptake in mouse colonic mucosa was Nathorn-dependent and saturable with Michaelis constant (K-m) of 2.4 mM. Na+-activation kinetics revealed that the Na+-to-5-ASA stoichiometry was 2:1 and concentration of Nathorn necessary for half-maximal transport (K-0.5(Na)) was 36.1 mM. Nathorn-dependent 5-ASA uptake was competitively inhibited by nicotinate with an inhibitory constant (K-i) of 2.1 mM was comparable to the K-m value of Nathorn-dependent nicotinate uptake (0.99 mM). Furthermore, ibuprofen, a selective SMCT1 inhibitor, was found to have a significantly inhibitory effect on the Nathorn-dependent 5-ASA uptake in mouse colon (IC50 = 0.19 mM). Taken collectively, these results indicated that SMCT1 in the mouse colonic mucosa is responsible for Nathorn-dependent 5-ASA uptake. (C) 2020 Elsevier Inc. All rights reserved.